The objective of this proposal is to determine the inhibitory effect of the combined treatments with 13-cis-retinoic acid and Alpha-difluoromethylornithine (DFMO) on 12-0-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor promotion. The application of either 13-cis-retinoic acid or DFMO in conjunction with promotion treatments of TPA to 7,12-dimethylbenz[a]anthracene (DMBA)-initiated skin inhibits skin tumor promotion by different mechanisms. 13-cis-Retinoic acid inhibits TPA-caused increased amount of ornithine decarboxylase (ODC) protein while DFMO is an enzyme-activated irreversible inhibitor (suicide inhibitor) of ODC; both inhibits TPA-induced accumulation of putrescin. Thus, we hypothesize that the combination of 13-cis-retinoic acid and DFMO may show enhanced inhibition of skin tumor promotion at dosage levels below the threshold for undesirable side effects of each when used singly. Specifically, we propose: 1. To delineate the optimal dose combination of 13-cis-retinoic acid and DFMO as given in the diet (13-cis-retinoic acid) and in the drinking water (DFMO) on both TPA-induced skin papillomas and carcinomas; and 2. To evaluate the toxic effects of 13-cis-retinoic acid and DFMO by determining effects on growth rate (body weight) and by a complete necropsy and histopathologic evaluation at the end of the experiment. CD-1 mouse skin tumors will be induced by the initiation (DMBA)-promotion (TPA)-protocol. Doses of 13-cis-retinoic acid and DFMO to be used in the tumor induction experiment will be determined from their inhibitory effect on TPA-caused accumulation of putrescine as determined by high-performance reversed-phase liquid chromatographic system. Every dead and killed mouse will receive a complete postmortem examination to observe the grossly detectable changes in the organs. Tissue samples will be fixed and stained for light microscopic examination of histopathological changes. Since 13-cis-retinoic acid is available for human use and the clinical use of DFMO is under investigation, the information obtained on the effects of combined treatments with 13-cis-retinoic acid and DFMO on tumor formation may be important for the use of these compounds for the prevention or the treatment of human cancer.